Amphiphile Lymph Node–Targeted Vaccine Is Safe and Bolsters T-Cell Responses in MRD+ PDAC and CRC

Administration of the adjuvant lymph node–targeted amphiphile vaccine ELI-002 7P at the recommended phase 2 dose (RP2D) was well tolerated and bolstered KRAS mutation (mKRAS)–specific T-cell responses in patients with minimal residual disease (MRD)–positive pancreatic and colorectal cancers, according to findings from the phase 1 AMPLIFY-7P trial (NCT05726864) presented during the 2024 ASCO Annual Meeting.¹

No dose-limiting toxicities, cytokine release syndrome, or other T-cell toxicities were reported with ascending doses of the amph-peptide antigen at either 1.4 mg (dose level 1) or 4.9 mg (dose level 2), administered alongside a fixed 10.0-mg dose of adjuvant amph-CpG-7909. All treatment-related adverse effects (AEs) were grade 1 and 2. Dose level 2 was accordingly identified as the RP2D, meeting the goal of the study.

At the optimized RP2D, ELI-002 7P resulted in more than an 8-fold increase in mKRAS-specific T-cell response vs the 1.4-mg dose (ELI-002 2P). Moreover, mKRAS-specific T-cell response rates were 100% with ELI-002 7P at the RP2D vs 84% with ELI-002 2P. Direct ex vivo T-cell response with dose level 1 of ELI-002 7P was a median of 9.3 times higher than baseline; this was comparable to that seen with ELI-002 in a prior report (median fold change = 12.75). At dose level 2, this was a median fold change of 109.20 from baseline. CD4 and CD8 T cells were generated in 59% and 66.7% of patients who received ELI-002 2P vs ELI-002 7P at the RP2D, respectively. Additionally, 66.7% of patients treated with the RP2D of ELI-002 7P responded to all 7 mKRAS antigens compared with 52.4% of those given ELI-002 2P.

“Lymph node targeting with [the] amphiphile vaccine is safe and induces potent T-cell responses 9-fold higher than observed in the prior study. The T-cell activity correlates with tumor biomarker reduction and antigen spreading,” lead study author Craig E. Devoe, MD, MS, chief of the division medical oncology and hematology at R. J. Zuckerberg Cancer

Center, in Lake Success, New York, stated during a poster presentation of the data. Devoe also serves as chief of the hematology-oncology service at Long Island Jewish Medical Center and at North Shore University Hospital.

Amphiphile lymph node–targeting technology was designed to improve both responses to, and the safety of, vaccination in this population. The approach enhances T-cell expansion, tumor infiltration, and functional quality compared with soluble vaccines, and has demonstrated long-term eradication of solid tumors in preclinical mouse models.

Data from the phase 1 AMPLIFY-201 trial (NCT04853017) of ELI-002 2P, the two-peptide formulation of this amphiphile lymph node–targeting vaccine, were published in Nature Medicine in 2024. Results showed that the vaccine was safe and induced both potent RAS-specific T-cell responses and tumor biomarker reductions in 84% of patients with pancreatic and colorectal cancers; this correlated with MRD clearance and prolonged relapse-free survival.²

Accordingly, investigators designed the AMPLIFY-7P trial to evaluate whether an 8-component formulation of the vaccine would extend the T-cell and antitumor benefits to patients harboring more diverse KRAS mutations.¹

“Our study uses immune therapy to target driver oncogene mutations of KRAS in the adjuvant setting for patients with pancreatic and colon cancer,” Devoe explained. “Previously engineered T cells recognizing KRAS are effective, but this approach is limited by the diversity of mutations required for targeting, and also by safety concerns.”

In this first-in-human safety and efficacy trial, the amphiphile vaccine was administered on a prime-and-boost schedule to patients with pancreatic ductal adenocarcinoma or colorectal cancer who have completed locoregional treatment, including chemotherapy and surgery with or without radiation; have no evidence of relapse on imaging; and are MRD positive. The presence of a KRAS G12(D, R, V, C, S, A) or G13D mutation was also required. The primary objective of the study was to determine the RP2D of the amph-peptide antigen.

Additional safety data demonstrated that any TRAEs were experienced by 78.6% of patients in the overall population (n = 14). The most common TRAEs across both dose levels were fatigue (42.9%) and malaise (21.4%), followed by diarrhea (21.4%), abdominal distension (14.3%), and abdominal pain (14.3%). Notably, 1 patient experienced a serious AE at dose level 1, resulting in hospitalization and withdrawal from treatment; however, this AE was not treatment related. No dose modifications were required, and no patients experienced TRAEs resulting in death or treatment discontinuation.

At a data cutoff date of December 18, 2023, 40% and 71% of evaluable patients (n = 12) at dose levels 1 and 2, respectively, displayed biomarker reduction or clearance; T-cell responses were observed in all 11 evaluable patients across both dose levels.

Antitumor activity was shown to correlate with T-cell response and dose levels. Of the 7 patients treated with the RP2D of ELI-002 7P, 5 displayed a decrease in biomarkers, 1 of whom achieved clearance. Biomarker reduction was observed in 2 of the 5 patients treated at dose level 1.

To date, patients who harbored all 4 RAS mutation variants (G12D, V, R, and G13D) achieved a response, as did patients with diverse HLA subtypes. Moreover, the strength of mKRAS-specific T-cell responses was found to correlate with tumor biomarker responses. Those with T-cell responses above a median fold change of 17.3 from baseline were deemed responders. Lower antitumor benefit was reported in patients who were below the median or did not achieve a T-cell response.

Over two-thirds of patients recruited additional T cells to join in antigen spreading, a process by which bystander T cells recognize personal tumor neoantigens not included in the vaccine. Frequent spreading of immune responses to non-mKRAS, personal tumor neoantigens was observed, with all 6 evaluable patients treated with the RP2D dose if ELI-002 demonstrated antigen spreading.

“We’re excited to see the evidence for antigen spreading, as a more diverse immune attack on the tumor might offer additional clinical benefit,” Devoe emphasized.

Based on these results, investigators have initiated the randomized phase 2 portion of the study assessing ELI-002 7P monotherapy in adjuvant PDAC. Disease-free survival will serve as the primary end point, and secondary end points include overall survival, tumor biomarker response, and safety.

“The patient eligibility has been broadened to include those with or without MRD relapse,” Devoe noted, adding that, “Those randomized to the initial observation arm will be permitted to cross over at the time they have confirmed radiographic progression.”

The study is expected to complete enrollment in 2024, with data from an interim analysis anticipated in the first quarter of 2025.

Disclosures: Dr Devoe reports the following disclosures: receiving honoraria from Vivacitas Oncology and serving in a consulting or advisory role for Pfizer.

References

1. Devoe CE, Pant S, Wainberg Z, et al. AMPLIFY-7P, a first-in-human safety and efficacy trial of adjuvant mKRAS-specific lymph node targeted amphiphile ELI-002 7P vaccine in patients with minimal residual disease–positive pancreatic and colorectal cancer. J Clin Oncol. 2024; 42(16): 2636. doi: 10.1200/JCO.2024.42.16_suppl.2636
2. Pant S, Wainberg ZA, Weekes CD, et al. Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial. Nat Med. 2024;30(2):531-542. doi:10.1038/s41591-023-02760-3